PACMED Salvage Therapy for Advanced High

Transcription

PACMED Salvage Therapy for Advanced High-Risk Multiple Myeloma (AHRMM)
Yazan Alsayed1, Sarah Waheed1, Jackie Szymonifka2, Bijay Nair1, Saad Usmani1, Frits van Rhee1, Elias Anaissie1,
Monica Grazziutti1, Antje Hoering2, and Bart Barlogie1
1Myeloma
Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR;
2 Cancer Research and Biostatistics, Seattle WA
Results: Response
Characteristics
Background
• High-risk MM remains a very difficult clinical
challenge despite advances in therapy for the majority
of patients who have benefited from the use of highdose therapies and novel agents.
• MM from the outset represents a genomically highly
complex malignancy with even further accelerated
acquisition of mutations with every further relapse
• We have tried to develop multi-agent combinations
employing drugs with efficacy in other high-grade
tumors such as large cell lymphomas and incorporated
novel agents as well.
Baseline Characteristics
N = 84
Age > 65 yr
UARK PACMED Patients Overall Survival by
Number of Risk Factors: Age >= 65 yr and LDH >= 190 U/L
18%
100%
B2M > 3.5 mg/L
60%
B2M > 5.5 mg/L
38%
CRP > 8 mg/L
60%
100%
80%
0
1
2
60%
40%
LDH > ULN
P < .0001
0
Eighty-four patients with AHRMM were given
PACMED
PACMED
Variable dosing/day
Schedule
CisPlatin
15 - 25 mg/m2
CI x 3d
CytArabine
1.0 - 1.5 mg/m2
x 3d
Cyclophosphamide
2
1.0 - 1.5 G/ m
CI x 3
Mesna
1.0 - 1.5 G/ m2
CI x 3
Etoposide
0.3 - 0.5 G/m
80%
GEP-defined 80 genes
71%
PR (Proliferation Subgroup)
44%
MF (MAF Subgroup)
27%
MS (MM set/FGFR3
Subgroup)
x 3d
Variable dosing/day
Schedule
Bortezomib
1.0 – 1.6 mg/m2
Days 1 & 4
Thalidomide
100 – 200 mg
Daily x 4d
Rapamycin
3mg
Day 1
Rapamycin
1 mg
Days 2-4
Stem Cell Boost
14%
2
Results: Risk Factor
P = .0003
0
1
Years from start of PACMED
2
Increased age and high LDH were the
only baseline characteristics adversely
affecting both OS and EFS [Table 1].
UARK PACMED Patients
Overall and Event-Free Survival
100%
1-Year
Events / N Estimate
80%
OS
66 / 84
13%
60%
EFS 71 / 84
8%
21%
80%
60%
40%
20%
0%
0
1
0%
2
Prior Transplant x 2
40%
25%
Prior Transplant > 3
14%
Cumulative Incidence of Response
1-Year
Events / N Estimate
>=Improvement
46 / 84
58%
>=Partial Response
24 / 84
31%
>=Near Complete Response 12 / 84
16%
Complete Response
7 / 84
9%
100%
20%
Overall Survival from start
of PACMED
Univariate
The corresponding values with 1 risk
factor (n=47) were 5%/4% and with
both risk factors (n=8) 0%/0%.
Conclusions
0
1
Table 1: Univariate and multivariate analyses for overall and event-free survival
Variable
The 29 patients with neither of these
risk factors experienced 1-yr OS/EFS
rates of 31%/17% [Figure 3a-b]
2
Single cycle PACMED provides only
transient tumor control in this heavily
pretreated population with 80% displaying
GEP-defined high-risk and 62% CA, as a
manifestation of end-stage MM.
With or without
Statistical methods included Cox regression
modeling for OS and EFS, along with KaplanMeier methodology for survival and cumulative
incidence plots. Survival comparisons were
made using the log rank test.
0%
1
40%
N = 81
x 3d
40 - 100 mg
Additional Agents
62%
GEP-defined 70 genes
Dexamethasone
60%
1-Year
Events / N Estimate
23 / 29
17%
40 / 47
4%
8/8
0%
Gene Expression
Characteristics
Transplant History: 96% of pts
2
0
1
2
20%
57%
Cytogenetic Abn
80%
40%
20%
0%
Materials & Methods
1-Year
Deaths / N Estimate
18 / 29
31%
40 / 47
5%
8/8
0%
UARK PACMED Patients Event-Free Survival by
1-year estimates of OS and EFS were
low at 13% and 8%, and median
durations were 5 and 3 months
[Figure 1].
PR was achieved by 29%, including 14%
n-CR and 8% CR [Figure 2].
Increased age and high LDH were the
only baseline characteristics adversely
affecting both OS and EFS [Table 1].
EventEvent-free Survival from
start of PACMED
N = 84
HR
P-value
HR
P-value
Age > 65 yrs
18%
3.18
< .001
2.00
0.035
LDH > 190 U/L
57%
2.62
< .001
2.08
0.004
CA within 1 yr
of start
62%
1.33
0.293
1.70
0.044
Age > 65 yrs
18%
3.52
< .001
2.20
0.017
LDH > 190 U/L
57%
2.75
< .001
2.17
0.002
Multivariate
We are currently evaluating repeated cycles
of PACMED earlier in the disease course in
high-risk MM, in the context of a SuperBEAM transplant regimen.
Acknowledgements
This work was supported by NIH P01 grant
#CA558919
We acknowledge the Myeloma Institute
Clinical and Research staff for their hard
work
PACMED Salvage Therapy for Advanced High-Risk Multiple Myeloma (AHRMM)
Yazan Alsayed1, Sarah Waheed1, Jackie Szymonifka2, Bijay Nair1, Saad Usmani1, Frits van Rhee1, Elias
Anaissie1,
1
Monica Grazziutti , Antje Hoering2, and Bart Barlogie1
1Myeloma
Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock,
AR;
2 Cancer Research and Biostatistics, Seattle WA
Figure 2: Cumulative incidence of response
BACKGROUND
High-risk MM remains a very difficult clinical challenge
despite advances in therapy for the majority of patients
who have benefited from the use of high-dose therapies
and novel agents.
MM from the outset represents a genomically highly
complex malignancy with even further accelerated
acquisition of mutations with every further relapse
We have tried to develop multi-agent combinations
employing drugs with efficacy in other high-grade tumors
such as large cell lymphomas and incorporated novel
agents as well.
PATIENTS AND METHODS
Eighty-four patients with AHRMM were given PACMED
comprising
Cisplatin (15-25mg/m2 CI x 3d)
Cytarabine (1.0-1.5g/m2/d x 3)
Cyclophosphamide (1.0-1.5g/m2/d CI x 3)
Mesna (1.0-1.5g/m2/d CI x 3)
Etoposide (0.3-0.5g/m2/d x 3)
Dexamethasone (40-100mg/d x 3)
Additional agents
Bortezomib (1.0-1.6mg/m2 on days 1 + 4)
Thalidomide (100-200mg/d x 4d) or lenalidomide (25100mg/d x 4)
Rapamycin (3mg d 1, 1mg d 2-4)
With or without HPC boost.
Statistical methods included Cox regression modeling
for Figure
OS and
EFS,and
along
with
Kaplan-Meier methodology for
1: Overall
event-free
survival
survival and cumulative incidence plots. Survival
UARK PACMED Patients Overall and Event-Free Survival
comparisons wereMedian
made
using
the log
Follow-Up
in Months:
7.8 rank test.
Most Recently Recorded Follow-Up Date, 08/04/10
100%
Overall survival
Event-free survival
80%
1-Year
Events / N Estimate
66 / 84 13% (5,22)
71 / 84 8% (2,15)
UARK PACMED Patients Cumulative Incidence of Response
100%
60%
40%
20%
0%
1-Year
Deaths / N Estimate
0
18 / 29 31% (11,50)
1
40 / 47
5% (0,11)
2
8/8
0% (0,23)
Logrank P-value < .0001
60%
40%
20%
0%
0
1
2
Figure 3b: Event-free survival by number of risk factors (Age > 65 yr,
LDH > 190 U/L)
100%
1-Year
Events / N Estimate
0
23 / 29 17% (3,31)
1
40 / 47 4% (0,11)
2
8/8
0% (0,23)
Logrank P-value = .0003
80%
60%
0%
2
2
80%
20%
1
1
100%
40%
0
0
Figure 3a: Overall survival by number of risk factors (Age > 65 yr,
LDH > 190 U/L)
40%
0%
1-Year
Events / N Estimate
58%
>=Improvement
46 / 84
31%
>=Partial Response
24 / 84
16%
9%
Complete Response
7 / 84
80%
60%
20%
Table 1: Univariate and multivariate analyses for overall and event-free
survival
0
1
2
RESULTS
Baseline characteristics included:
 Age >=65 in 18%
 B2M >=3.5mg/L in 68% and >5.5mg/L in 38%
CRP >=8mg/L in 60%
LDH >=ULN in 57%
Cytogenetic abnormalities (CA) in 62%.
 Gene expression profiling (GEP)-defined high-risk (70
genes, R70; 80 genes, R80) was present in 80% and 71%
PR (Proliferation), MF and MS subtypes were present in
44%, 27% and 14%.
Prior transplants (Tx) had been given to 96%, including
40% who received two Tx, 25% with three Tx and 14%
with more than 3 Tx.
1-year estimates of OS and EFS were low at 13% and
8%, and median durations were 5 and 3 months [Figure 1].
PR was achieved by 29%, including 14% n-CR and 8% CR
[Figure 2].
Increased age and high LDH were the only baseline
characteristics adversely affecting both OS and EFS
[Table 1].
The 29 patients with neither of these risk factors
experienced 1-yr OS/EFS rates of 31%/17% [Figure 3a-b]
The corresponding values with 1 risk factor (n=47) were
5%/4% and with both risk factors (n=8) 0%/0%.
CONCLUSION
Single cycle PACMED provides only transient tumor
control in this heavily pretreated population with 80%
displaying GEP-defined high-risk and 62% CA, as a
manifestation of end-stage MM.
We are currently evaluating repeated cycles of PACMED
Number of Risk Factors: Age >= 65 yr and LDH >= 190 U/L Number of Risk Factors: Age >= 65 yr and LDH >= 190 U/L
100%
0
1
2
80%
100%
1-Year
Deaths / N Estimate
18 / 29
31%
40 / 47
5%
8/8
0%
0
1
2
80%
60%
60%
40%
40%
1-Year
Events / N Estimate
23 / 29
17%
40 / 47
4%
8/8
0%
20%
20%
P < .0001
0%
0
1
0%
2
P = .0003
0
100%
1-Year
Events / N Estimate
OS
66 / 84
13%
EFS 71 / 84
8%
80%
60%
80%
60%
40%
40%
20%
20%
0%
0
1
2
Cumulative Incidence of Response
1-Year
Events / N Estimate
>=Improvement
46 / 84
58%
>=Partial Response
24 / 84
31%
16%
Complete Response
7 / 84
9%
Overall and Event-Free Survival
100%
1
2
0%
0
1
2

PACMED Salvage Therapy for Advanced High

Transcription

Similar documents